Three of the most highly expressed drug-metabolizing enzymes in rabbit lung are cytochrome P-450 isozymes IIB and IVB and the flavin-containing monooxygenase (FMO). Together these enzymes metabolize a wide variety of drugs, pesticides and other environmental chemicals. In addition to oxidation at carbon atoms, this group of enzymes also oxidizes sulfur, phosphorous and nitrogen. Drug-metabolizing enzymes may be involved in the activation of certain chemicals whose toxic effects are pulmonary specific. Because similar enzymes are also expressed in liver, the observation of tissue-specific effects suggests that different forms of the enzymes may be expressed in the two tissues. The liver/lung expression of P-450 IIB turns out to be quite complicated. Multiple forms of the enzyme having greater than 97% identity exist. However, one of the forms is expressed only in liver. This has been demonstrated by us in rabbit and hamster and by others in rat. This finding indicates that control of expression developed prior to speciation and that the structural portions of the different genes for IIB must undergo interconversion. In contrast to IIB, P-450 IVB may be encoded for by only a single gene. It is of interest that the 5'-flanking region of the rabbit IVB gene is not similar to the same region of the human gene. These differences may be important in the exclusion of IVB from human liver but not from rabbit liver. Previously, we have defined the differences between the structures of the FMO enzymes expressed in liver and lung. These enzymes, which are 56% identical, are clearly products of different genes. Hybrid proteins formed by combinations of the liver and lung cDNAs are expressed in COS cells but are inactive even though the secondary structures of the enzymes appear to be highly similar. Also, in examining some physical properties of the expressed FMO enzymes, we have noted that the liver enzyme does not retain the temperature sensitivity that it exhibits in hepatic microsomes. Presently, we are constructing a series of lung/liver and liver/liver chimerics in order to further investigate the catalytic properties of the FMO enzymes.